US2002052380A1PendingUtilityA1
Inhibitors of prenyl-protein transferase
Priority: Feb 18, 2000Filed: Jan 26, 2001Published: May 2, 2002
Est. expiryFeb 18, 2020(expired)· nominal 20-yr term from priority
C07D 403/06
38
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Claims
Abstract
The present invention comprises piperazinone-containing compounds, which may be useful as inhibitors of prenyl-protein transferases, including farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such therapeutic compounds are useful in the treatment of cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound which is illustrated by formula A:
wherein:
R 1a and R 1b are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, R 10 P—, R 11 S(O) m ,—, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 O—, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, or
c) unsubstituted or substituted C 1 -C 6 alkyl wherein the substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, R 10 O—, R 11 S(O) m —, R 10 OC(O)NR 10 O—, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 OC(O)—, R 10 C(O)—, —N(R 10 ) 2 , and R 11 OC(O)NR 10 —;
R 2 and R 3 are independently selected from: H, unsubstituted or substituted C 1 -6 alkyl, unsubstituted or substituted C 2 -8 alkenyl, unsubstituted or substituted C 2 -8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C 1 -6 alkyl,
b) (CH 2 ) p OR 6 ,
c) (CH 2 ) p NR 6 R 7 ,
d) halogen,
e) CN,
2) C 3 -6 cycloalkyl,
3) OR 6 ,
4) SR 6a , S(O)R 6a , SO 2 R 6a ,
5) —NR 6 R 7
R 2 and R 3 are attached to the same C atom and are combined to form —(CH 2 ) u — wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , —NC(O)—, and —N(COR 10 )—;
R 4 is selected from H and unsubstituted or substituted C 1 -C 6 alkyl;
and any two of R 2 , R 3 or R 4 are optionally attached to the same carbon atom;
R 5 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, unsubstituted or substituted C 1 -C 6 alkoxy, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl, unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
provided that R 5 is not hydrogen if Y is aryl and t is 1;
R 6 , R 7 and R 7a are independently selected from: H, C 1 -C 6 alkyl, C 3 -6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1 -6 alkoxy,
b) C 1 -C 20 alkyl
c) aryl or heterocycle,
d) halogen,
e) HO,
f) —C(O)R 11 ,
g) —SO 2 R 11 , or
h) N(R 10 ) 2 ; or
R 6 and R 7 may be joined in a ring;
R 7 and R 7a may be joined in a ring;
R 6a is selected from: C 1 -C 6 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) C 1 -C 20 alkyl
c) aryl or heterocycle,
d) halogen,
e) HO,
f) —C(O)R 11 ,
g) —SO 2 R 11 , or
h) N(R 10 ) 2 ;
R 8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, unsubstituted or substituted C 1 -C 6 alkoxy, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, NO 2 ,
R 1 OC(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 9 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, perfluoroalkyl, halo, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 10 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, perfluoroalkyl, unsubstituted or substituted aralkyl, and unsubstituted or substituted aryl;
R 11 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl and unsubstituted or substituted aryl;
A 1 and A 2 are independently selected from: a bond, —CH═CH—, —C≡C—, —C(O)—, —C(O)NR 10 —, —NR 10 C(O)—, O, —N(R 10 )—, —S(O) 2 N(R 10 )—, —N(R 10 )S(O) 2 —, or S(O) m ;
A 3 is selected from —C(O)—, —C(R 1a ) 2 —, O, —N(R 10 )— and S(O) m ;
G 1 or G 2 is selected from H 2 or O, provided that if G 1 is O then G 2 is H 2 and if G 2 is O, then G 1 is H 2 ;
V is selected from:
a) heterocycle, and
b) aryl,
W is a heterocycle;
Y is aryl;
Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1 ) C 1 -C 6 alkyl, unsubstituted or substituted with:
a) C 1-6 alkoxy, b) NR 6 R 7 , c) C 3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O) m R 6a , or g) —C(O)NR 6 R 7 ,
2) unsubstituted or substituted aryl or unsubstituted or substituted heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ;
9) —S(O) m R 6a ,
10) —C(O)NR 6 R 7 ,
11) —OCF 3 ,
12) unsubstituted or substituted C 1-6 alkoxy,
13) C 2 -C 8 alkenyl,
14) C 2 -C 8 alkynyl, or
15) C 3 -C 10 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5;
s is 0 or 1;
t is 0 to 5;
u is 4 or 5; and
x is 0, 1, 2, 3 or 4;
or the pharmaceutically acceptable salts or optical isomers thereof.
2 . The compounds according to claim 1 , as illustrated by formula B:
wherein:
R 1a and R 1b are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, R 10 O—, —N(R 10 ) 2 , or, C 2 -C 8 alkenyl, or
c) unsubstituted or substituted C 1 -C 6 alkyl wherein the substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, C 2 -C 8 alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 2 and R 3 are independently selected from: H, unsubstituted or substituted C 1-6 alkyl, or
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C 1 -C 6 alkyl,
b) (CH 2 ) p OR 6 ,
c) (CH 2 ) p NR 6 R 7 ,
d) halogen,
e) CN,
2) C 3-6 cycloalkyl,
3) OR 6 ,
4) SR 6a , S(O)R 6a , SO 2 R 6a ,
5) —NR 6 R 7
15) N 3 , or
16) F; or
R 2 and R 3 are attached to the same C atom and are combined to form —(CH 2 ) u — wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , —NC(O)—, and —N(COR 10 )—;
R 4 is selected from H and unsubstituted or substituted C 1 -C 6 alkyl;
and any two of R 2 , R 3 or R 4 are optionally attached to the same carbon atom;
R 5 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, unsubstituted or substituted C 1 -C 6 alkoxy, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O—, R 11 S(O) m —, R 1 OC(O)NR 10 O—, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
provided that R 5 is not hydrogen if Y is aryl and t is 1;
R 6 , R 7 and R 7a are independently selected from: H, C 1 -C 6 alkyl, C 3 -6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-6 alkoxy,
b) C 1 -C 20 alkyl
c) aryl or heterocycle,
d) halogen,
e) HO,
f) —C(O)R 11 ,
g) —SO 2 R 11 , or
h) N(R 10 ) 2 ; or
R 6 and R 7 may be joined in a ring;
R 7 and R 7a may be joined in a ring;
R 6a is selected from: C 1 -C 6 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-6 alkoxy,
b) C 1 -C 20 alkyl
c) aryl or heterocycle,
d) halogen,
e) HO,
f) —C(O)R 11 ,
g) —SO 2 R 11 , or
h) N(R 10 ) 2 ; or
R 8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, unsubstituted or substituted C 1 -C 6 alkoxy, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 10 C(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 9 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, R 10 2 N-C(NR 10 )—, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, N 3 , —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, perfluoroalkyl, halo, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 10 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, perfluoroalkyl, unsubstituted or substituted aralkyl, and unsubstituted or substituted aryl;
R 11 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl and unsubstituted or substituted aryl;
A 1 and A 2 are independently selected from: a bond, —CH═CH—, —C≡C—, —C(O)—, —C(O)NR 10 —, —NR 10 C(O)—, O, —N(R 10 )—, —S(O) 2 N(R 10 )—, —N(R 10 )S(O) 2 —, or S(O) m ;
A 3 is selected from —C(0)—, —C(R 1a ) 2 —, 0, —N(R 10 )- and S(O) m ;
W is a heterocycle selected from imidazolyl, pyridyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl and thienyl;
Y is aryl;
Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1) C 1 -C 6 alkyl, unsubstituted or substituted with:
a) C 1-6 alkoxy,
b) NR 6 R 7 ,
c) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) —S(O) m R 6a , or
g) —C(O)NR 6 R 7 ,
2) unsubstituted or substituted aryl or unsubstituted or substituted heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ;
9) —S(O) m R 6a ,
10) —C(O)NR 6 R 7 ,
11) C 3 -C 6 cycloalkyl,
12) —OCF 3 , or
13) unsubstituted or substituted C 1-6 alkoxy;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or2;
r is 0 to 5;
t is 0 to 5;
u is 4 or 5; and
x is 0, 1, 2, 3 or 4;
or the pharmaceutically acceptable salts or optical isomers thereof.
3 . The compound according to claim 1 of the formula C:
wherein:
R 1a and R 1b are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, R 10 O—, or —N(R 10 ) 2 , or
c) unsubstituted or substituted C 1 -C 6 alkyl wherein the substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, C 2 -C 8 alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 2 is H, unsubstituted or substituted C 1-6 alkyl, or
wherein the substituted group is substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR 6 ,
4) SR 6a , SO 2 R 6a , or
5)
R 3 and R 4 are independently selected from H and unsubstituted or substituted C 1 -C 6 alkyl;
and any two of R 2 , R 3 or R 4 are optionally attached to the same carbon atom;
R 5 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, unsubstituted or substituted C 1 -C 6 alkoxy, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C 3 -C 10 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
provided that R 5 is not hydrogen if Y is aryl and t is 1;
R 6 and R 7 are independently selected from: H, C 1 -C 6 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C 1-6 alkoxy,
b) C 1 -C 20 alkyl
c) aryl or heterocycle,
d) halogen, or
e) HO;
R 6 and R 7 may be joined in a ring;
R 6a is selected from: C 1 -C 6 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-6 alkoxy,
b) C 1 -C 20 alkyl
c) aryl or heterocycle,
d) halogen, or
e) HO;
R 8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, unsubstituted or substituted C 1 -C 6 alkoxy, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C 3 -C 10 cycloalkyl, perfluoroalkyl, halo, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 9 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 8 alkenyl, unsubstituted or substituted C 2 -C 8 alkynyl, perfluoroalkyl, halo, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, perfluoroalkyl, halo, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, (R 10 ) 2 NC(O)NR 10 —, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 10 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, perfluoroalkyl, unsubstituted or substituted aralkyl, and unsubstituted or substituted aryl;
R 11 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl and unsubstituted or substituted aryl;
A 3 is selected from —C(O)—, —C(R 1a ) 2 —, O, —N(R 10 )— and S(O) m ;
Y is aryl;
Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, wherein the substituted group is substituted with one or more of the following:
1) C 1 -C 6 alkyl, unsubstituted or substituted with:
a) C 1-6 alkoxy,
b) NR 6 R 7 ,
c) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) —S(O) m R 6a , or
g) —C(O)NR 6 R 7 ,
2) unsubstituted or substituted aryl or unsubstituted or substituted heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ;
9) —S(O) m R 6a ,
10) —C(O)NR 6 R 7 ,
11) C 3 -C 6 cycloalkyl,
12) —OCF 3 , or
13) unsubstituted or substituted C 1-6 alkoxy;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5;
t is 0 to 5; and
u is 4 or 5;
or the pharmaceutically acceptable salts or optical isomers thereof.
4 . A compound which is selected from:
1-(3-chlorophenyl)-4-[1-(3-((2-chlorophenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; 1-(3-chlorophenyl)-4-[1-(3-((3-chlorophenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; 1-(3-chlorophenyl)-4-[1-(3-((4-chlorophenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; 1-(3-chlorophenyl)-4-[1-( 3 -((4-biphenylyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; 1-(3-chlorophenyl)-4-[1-(3-((3-(2-hydroxy- 1-ethoxy)phenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; 1-(3-chlorophenyl)-4-[1-(3-((4-(benzyloxy)phenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; and 1-(2-(n-Butyloxy)phenyl)-4-[1-(3-((3-(2-hydroxy-1-ethoxy)phenyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone or the pharmaceutically acceptable salts or optical isomers thereof.
5 . The compound according to claim 4 which is
1-(3-chlorophenyl)-4-[1-(3-((2-chlorophenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone
or the pharmaceutically acceptable salts or optical isomers thereof.
6 . The compound according to claim 4 which is
1-(3-chlorophenyl)-4-[1-(3-((3-chlorophenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone
or the pharmaceutically acceptable salts or optical isomers thereof
7 . The compound according to claim 4 which is
1-(3-chlorophenyl)-4-[1-(3-((4-chlorophenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone
or the pharmaceutically acceptable salts or optical isomers thereof.
8 . The compound according to claim 4 which is
1-(3-chlorophenyl)-4-[1-(3-((4-biphenylyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone
or the pharmaceutically acceptable salts or optical isomers thereof.
9 . The compound according to claim 4 which is
1-(3-chlorophenyl)-4-[1-(3-((3-(2-hydroxy- 1-ethoxy)phenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone
or the pharmaceutically acceptable salts or optical isomers thereof.
10 . The compound according to claim 4 which is
1-(3-chlorophenyl)-4-[1-(3-((4-(benzyloxy)phenyl)oxy)-4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone
or the pharmaceutically acceptable salts or optical isomers thereof.
11 . The compound according to claim 4 which is
1-(2-(n-Butyloxy)phenyl)-4-[1-(3-((3-(2-hydroxy-1-ethoxy)phenyl)oxy)-4-cyanobenzyl)-2-methyl-5-midazolylmethyl]-2-piperazinone
or the pharmaceutically acceptable salts or optical isomers thereof.
12 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .
13 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 2 .
14 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 4 .
15 . A method for inhibiting farnesyl-protein transferase and geranylgeranyl-protein transferase type I which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
16 . A method for inhibiting farnesyl-protein transferase and geranylgeranyl-protein transferase type I which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 2 .
17 . A method for inhibiting farnesyl-protein transferase and geranylgeranyl-protein transferase type I which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 4 .
18 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
19 . A method according to claim 18 wherein the cancer is characterized by a mutated K4B -Ras protein.
20 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound claim 1 .
21 . A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
22 . A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
23 . A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
24 . A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
25 . A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.
26 . A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.Join the waitlist — get patent alerts
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